Our laboratory has observed abnormalities in resting-state (RS) and auditory neural activity in children with autism spectrum disorder (ASD). There is a clinical component to these findings, with RS and auditory brain rhythms predicting symptom severity. There is a developmental/maturational component, with age cross-sectional findings indicating greater clinical impairment in the children with ASD with the most delayed maturation of RS and auditory processes. Finally, there is a structural component, with our analyses demonstrating thalamic involvement in RS and auditory neural abnormalities. Given the central role of the thalamus in modulating and coordinating neural activity, understanding the contribution of thalamic structure and thalamocortical connectivity to cortical oscillatory abnormalities in ASD is of high priority. This proposed R01 will demonstrate that neural dysfunction and clinical symptoms in ASD arise, in part, from abnormal thalamic and thalamocortical structure. A primary tenet of this proposal is that understanding brain dysfunction in children with ASD requires assessing developmental processes rather than a single time-point (snapshot) measure. To this end, a three time-point longitudinal study is proposed, with brain and clinical measures obtained in typically developing control (TDC) and ASD participants aged 6- to 8-years and then both 18 and 36 months later (N=70 per group at enrollment). It is hypothesized that children with ASD will show slower development of brain rhythms/patterns, with rate of change (i.e. slope) rather than single time-point measures better separating TDC and ASD. It is also hypothesized that rate of change rather than single time-point measures will better predict functional capacity, with baseline measures demonstrating pathology (e.g., auditory processing abnormalities) but with rate-of-change indicating the degree of successful brain maturation and thus offering greater prognostic utility. It is expected that R0 findings will offer conceptual innovation by motivating the need to develop 'thalamic therapies', with R01 human neural and associated thalamocortical white-matter abnormalities back-translated to animal models, and with animal research identifying potential pharmaceutical treatments. Animal work will likely build on current gene and neural stem cell therapy research. Pro-myelinating therapies and image-guided deep brain stimulation or other target-based neuro-modulation treatments may also be of future interest.

Public Health Relevance

Although theories of autism spectrum disorder (ASD) implicate a contribution of thalamic pathology to neural oscillatory rhythms in ASD (thalamocortical dysrhythmia), no study has directly examined this hypothesis. Recruiting children with ASD and typically developing children, via a longitudinal design, the proposed R01 uses multimodal imaging and advanced signal processing to examine the maturation of brain function and structure measures as well as to examine the contribution of thalamic structure and thalamocortical pathways to cortical neural oscillations as well as functional capacity in ASD. Given the central role of the thalamus in modulating and coordinating brain neural activity, understanding the contribution of the thalamus to cortical oscillatory abnormalities in ASD is of high priority.